EP3270153B1 - Procédés de fonctionnement d'un système comprenant un spectromètre de masse, spectromètre de mobilité ionique et chromatographe - Google Patents

Procédés de fonctionnement d'un système comprenant un spectromètre de masse, spectromètre de mobilité ionique et chromatographe Download PDF

Info

Publication number
EP3270153B1
EP3270153B1 EP17185084.5A EP17185084A EP3270153B1 EP 3270153 B1 EP3270153 B1 EP 3270153B1 EP 17185084 A EP17185084 A EP 17185084A EP 3270153 B1 EP3270153 B1 EP 3270153B1
Authority
EP
European Patent Office
Prior art keywords
ion
faims
spectrometer
ions
precursor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP17185084.5A
Other languages
German (de)
English (en)
Other versions
EP3270153A1 (fr
Inventor
Satendra PRASAD
Jean-Jacques Dunyach
Michael W. Belford
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Thermo Finnigan LLC
Original Assignee
Thermo Finnigan LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Thermo Finnigan LLC filed Critical Thermo Finnigan LLC
Publication of EP3270153A1 publication Critical patent/EP3270153A1/fr
Application granted granted Critical
Publication of EP3270153B1 publication Critical patent/EP3270153B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
    • G01N27/622—Ion mobility spectrometry
    • G01N27/624—Differential mobility spectrometry [DMS]; Field asymmetric-waveform ion mobility spectrometry [FAIMS]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/0027—Methods for using particle spectrometers
    • H01J49/0031—Step by step routines describing the use of the apparatus
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/004—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn

Definitions

  • the present invention relates generally to the field of mass spectrometry and, more particularly, relates to a system comprising a mass spectrometer apparatus that is coupled to and receives ions from an ion-mobility spectrometer, such as a high-field asymmetric ion mobility spectrometer (FAIMS) apparatus.
  • a mass spectrometer apparatus that is coupled to and receives ions from an ion-mobility spectrometer, such as a high-field asymmetric ion mobility spectrometer (FAIMS) apparatus.
  • FAIMS high-field asymmetric ion mobility spectrometer
  • the LC/MS technique generally provides data in the form of a mass chromatogram, in which detected ion intensity (a measure of the number of detected ions) as measured by a mass spectrometer is given as a function of time.
  • detected ion intensity a measure of the number of detected ions
  • various separated chemical constituents elute from a chromatographic column as a function of time. As these constituents elute off the column, they are submitted for mass analysis by a mass spectrometer at which each analyte or chromatographic fraction is ionized, generally producing a variety of ions from each such analyte or fraction.
  • the mass spectrometer accordingly generates, in real time, detected relative ion abundance data for ions produced from each eluting analyte or each chromatographic fraction, in turn.
  • liquid chromatography includes, without limitation, reverse phase liquid chromatography (RPLC), hydrophilic interaction liquid chromatography (HILIC), high performance liquid chromatography (HPLC), ultra high performance liquid chromatography (UHPLC), normal-phase high performance liquid chromatography (NP-HPLC), supercritical fluid chromatography (SFC) and ion chromatography.
  • RPLC reverse phase liquid chromatography
  • HILIC hydrophilic interaction liquid chromatography
  • HPLC high performance liquid chromatography
  • UHPLC ultra high performance liquid chromatography
  • NP-HPLC normal-phase high performance liquid chromatography
  • SFC supercritical fluid chromatography
  • ion chromatography ion chromatography
  • MS/MS tandem mass spectrometry
  • a parent (or precursor) ion generated from a molecule of interest can be filtered or isolated in an MS instrument (for instance, in a quadrupole mass filter, Q1, of a triple quadrupole instrument), and these precursor ions are subsequently fragmented (e.g., in a second quadrupole, Q2) to yield multiple product or fragment ions that are then analyzed in a downstream MS stage (e.g., in a third quadrupole, Q3).
  • a chromatographic peak having an approximately 12 second width at its base is mass analyzed by the MRM technique and the MRM precursor isolation list includes 100 m / z species to be targeted during an LC analysis.
  • the 100 m / z isolations are represented by square blocks at the base of FIG. 8 .
  • Each of the vertical lines illustrated underneath the chromatographic peak profile 200 represents a single, representative first mass spectral MS/MS analysis out of 100 such analyses per cycle.
  • the analysis start may be chosen to correspond to some well-defined event, such as the opening of a valve that begins the flow of chromatographic mobile phase through a chromatographic column. A consistent definition of the starting event enables comparison of results across separate experiments.
  • the time increment between each pair of vertical lines in the top portion of FIG. 8 represents the cumulative time needed to step through all the 100 MS/MS analyses - each corresponding to a different respective m / z isolation - and is termed the cycle time.
  • the process is iterative; thus, a new sweep through the full list is initiated at the time indicated by each vertical line.
  • This iterative analytical process terminates at the end of an LC gradient.
  • LC-MRM analysis is a popular technique for quantifying constituents - such as proteins and peptides in biological samples - whose abundances may vary by orders of magnitude. At low abundance, the quality of quantitation is dependent on ion statistics or by the % RSD of the integral of the analyte response.
  • An analytically acceptable % RSD of ⁇ 15% often requires at least 10 MS/MS analyses. For instance, assume that the Q1 dwell time required to perform a single MS/MS analysis is equal to 10 ms and that the inter-analysis delay is 2.0 ms. These instrumental parameters correspond to a cycle time of ⁇ 1.2 seconds per cycle, which is the time required to cycle through the 100 precursor/product ion pairs in the MRM list. Thus, during the elution of a ⁇ 12-second wide peak, which is typical for nano-flow rate chromatography, a total of 10 mass spectral analyses can be acquired for each such ion pair.
  • a key difference between a MRM analysis and other types of tandem LC/MS analyses is that, in a MRM analysis, the detection of a precursor ion m / z is not a criterion to initiate a MRM event.
  • the mass analyzer continuously cycles through a predetermined list of precursor-product ion pairs over the duration of a LC gradient.
  • a precursor ion species of interest must be detected in a low collision energy pre-scan or MS survey scan.
  • the survey scan reveals high-abundance precursor ions that are selected for dissociation and the product ions are analyzed in a MS/MS scan mode.
  • the precursor ions are not predetermined (MRM) but, rather, detected during the survey scan.
  • Data-dependent acquisition methods may be characterized as having one or more input criteria, and one or more output actions.
  • the input criteria employed for conventional data-dependent methods are generally based on parameters such as intensity, intensity pattern, mass window, mass difference (neutral loss), mass-to-charge ( m / z ) inclusion and exclusion lists, and product ion mass.
  • the input criteria are employed to select one or more ion species that satisfy the criteria.
  • the selected ion species are then subjected to an output action (examples of which include performing MS/MS or MS n analysis and/or high-resolution scanning).
  • a group of ions is mass analyzed, and ion species having mass spectral intensities exceeding a specified threshold are subsequently selected as precursor ions for MS/MS analysis, which may involve operations of isolation, dissociation of the precursor ions, and mass analysis of the product ions.
  • FIMS High Field Asymmetric Waveform Ion Mobility Spectrometry
  • DMS Differential Ion Mobility Spectrometry
  • a FAIMS cell comprises a pair of spaced apart electrodes that define therebetween a separation region through which a stream of ions is directed.
  • An asymmetric oscillatory voltage waveform comprising a high voltage component and a lower voltage component of opposite polarity, together with a non-oscillatory DC voltage (referred to as the compensation voltage, or CV) is applied to one of the electrodes.
  • FIG. 1 schematically depicts a first known system 100 for analyzing ions that includes a FAIMS device 155 coupled to a mass spectrometer 157 .
  • the known FAIMS device 155 illustrated in FIG. 1 is an example of a type of device that has been referred to as a "side-to-side FAIMS" or a "perpendicular-gas-flow-FAIMS" (e.g., see U.S. Patent No. 6,713,758 and international application publication No. WO01/69216 ).
  • a solution of sample to be analyzed is introduced as a spray of liquid droplets into an ionization chamber 105 via atmospheric pressure ion source 110.
  • Ionization chamber 105 is maintained at a high pressure relative to the regions downstream in the ion path, typically at or near atmospheric pressure.
  • Atmospheric pressure ion source 110 may be configured as an electrospray ionization (ESI) probe, wherein a high DC voltage (either positive or negative) is applied to the capillary or "needle" through which the sample solution flows.
  • ESI electrospray ionization
  • APCI atmospheric pressure chemical ionization
  • HESI heated electrospray ionization
  • thermospray ionization thermospray ionization
  • Ions produced by the ion source enter the FAIMS cell 155 through an aperture 117 in an entrance plate 120 and then through an inlet orifice 150 after passing through an expansion chamber 111 .
  • the expansion chamber is provided with a gas, typically helium or other inert gas, which is introduced into the expansion chamber 111 via a gas conduit 113 .
  • a portion of the gas flows back into the ionization chamber 105 through entrance plate aperture 117 in counter-flow to the ions and droplets and serves to desolvate charged droplets.
  • Another portion of the gas combines with the analyte ions in chamber 111 and serves as a carrier gas through the FAIMS cell 155 .
  • the combined ion/carrier gas flow then enters FAIMS cell 155 through inlet orifice 150 .
  • the carrier gas flow may be carefully metered to maintain flow rates within predetermined limits which will depend on the FAIMS cell size, electrode geometry, and operational considerations.
  • An electrical potential difference is maintained between the entrance plate 120 and the FAIMS cell 155 and, thus, physical separation is maintained between these components.
  • a non-conducting sealing element 173 such as a gasket or O-ring maintains the FAIMS gas within the apparatus and prevents contamination of this gas from outside air. Because of drawing-space limitations, this sealing element is not explicitly shown in some of the accompanying drawings.
  • the side-to-side FAIMS cell 155 includes inner and outer electrodes 165 and 170 having radially opposed surfaces, which define therebetween an annular separation region 175 (an “analytical gap") through which the ions are transported.
  • the side-to-side FAIMS cell geometry depicted in FIG. 1 as well as in other figures herein provides a configuration in which the longitudinal axes (axes of cylindrical surfaces, directed out of the page) of inner electrode 165 and outer electrode 170 are oriented transversely with respect to the overall direction of ion flow.
  • the principles of the design and operation of FAIMS cells and other ion mobility spectrometry devices have been extensively described elsewhere in the art (see, for example, U.S. Pat. No.
  • the carrier gas and ions flow through the separation region 175 from inlet orifice 150 to exit orifice 185 .
  • Ion separation is effected within the separation region (analytical gap) 175 of the FAIMS cell 155 by applying an asymmetric waveform having a peak voltage (DV) and a compensation voltage (CV) to one of the inner or outer electrodes, 165 , 170 .
  • the values of CV and DV are set to allow transmission of a selected ion species through separation region 175 .
  • Other ion species having different relative values of high field and low field mobilities will migrate to the surface of one of the electrodes and will be neutralized.
  • the inlet orifice 150 of the conventional FAIMS apparatus 155 comprises a simple hole of circular cross section having a constant inner diameter.
  • U.S. Patent No. 8,664,593 which is assigned to the assignee of the instant invention, described side-to-side FAIMS apparatuses having curved ion inlet orifices, which provide for more efficient transfer of analyte ions through the analytical gap.
  • FIG. 2 shows the FAIMS gas flow into an electrode set that is provided with a so-modified ion inlet orifice.
  • the modified ion inlet orifice acts to decrease the volume and rate of gas flow directly onto the inner electrode adjacent to the orifice, thus significantly reducing neutralization of analyte ions.
  • the inner electrode 165 is generally a right-circular cylindrical rod having an axis 177 that is parallel to the length of the rod (see FIG. 5A ).
  • the axis 177 is perpendicular to the plane of the drawing and is thus indicated as a piercing point ("+" symbol).
  • the FAIMS apparatus 109 that is schematically illustrated in FIG. 2 is generally similar to the FAIMS apparatus 155 shown in FIG. 1 except with regard to the shape of the ion inlet orifice.
  • Inset 30 of FIG. 2 illustrates an enlarged view of the vicinity of the ion inlet orifice 151 of the FAIMS 109 .
  • the walls 31 of the ion inlet orifice 151 of the FAIMS apparatus 109 are convexly curved between the orifice inlet end 32 and the orifice outlet end 33 .
  • the inner diameter of the ion inlet orifice is at a minimum value within the orifice.
  • the inner diameter of the ion inlet orifice 151 smoothly increases or flares outward in both directions (i.e., towards the two ends of the orifice or, equivalently, towards and away from the inner electrode 177 ) away from the region of minimum diameter.
  • the gas flow in the vicinity of the rounded walls of the ion inlet orifice 151 demonstrates the so-called Coand effect, which is the general tendency of a fluid jet to be drawn towards and follow the contour of a curved solid surface.
  • the carrier gas flow entering the analytical gap 175 of the FAIMS apparatus 109 ( FIG. 2 ) is kept closer to the curvature of the entrance orifice than would otherwise be the case.
  • This behavior allows for incorporation of the gas stream into the gap and away from the inner electrode as is indicated in FIG. 2 by the smooth divergence of gas flow vectors away from the center electrode 165 and into the analytical gap 175 .
  • the smooth divergence of the carrier gas into away from the center electrode and into the analytical gap 175 is expected to urge ions along similar pathways, thereby reducing the proportion of ions that are lost as a result of collision with the center electrode and improving ion transmission through the FAIMS apparatus.
  • the smooth divergence also leads to a larger zone of laminar flow within the analytical gap, with reduced recirculation flow near the entrance orifice.
  • FIG. 3 shows the results of combined fluid dynamic and ion trajectory modeling, through the FAIMS apparatus 109 .
  • FIG. 4 shows a comparison between the transmission efficiency (curve 42 ) of the apparatus having the curved an inlet orifice 151 and shown in FIG. 3 with that of the prior FAIMS apparatus shown in FIG. 1 (curve 44 ). It is evident from the shape of the ion cloud 129 in FIG. 3 that the curved orifice design promotes a smooth bifurcation of ion flow prior around the center electrode 165 and into the analytical gap 175 . The smooth flow bifurcation appears to have the effect of reducing gas recirculation flow with the analytical gap just after passing through the inlet orifice, thereby significantly reducing ion neutralization at both inner and outer electrodes.
  • a mass analyzer that receives ions from a FAIMS apparatus should remain set to detect only the m / z value of a particular analyte ion species of interest during the entire time that the FAIMS is operated so as to transmit ions having the particular differential ion mobility associated with that particular analyte ion species. If the mass analyzer were to be set to detect a different m / z ratio during this time, generally no ions would be detected, since the FAIMS would generally eliminate all other ion species, based on their various values of differential ion mobility.
  • the FAIMS residence time thus defines the period that the first mass analyzer (Q1) must spend on a single mass-to-charge ratio ( m / z ) isolation.
  • Q1 only requires, at most, a few tens of milliseconds, in the absence of a FAIMS pre-filter, to isolate or filter ions comprising a single m / z range, thus permitting analysis of up to ⁇ 100 or more isolations per second.
  • increasing the Q1 dwell time in order to match the 50-100 ms residence time of the conventional FAIMS apparatus may result in insufficient number of scans to define a stable chromatographic peak structure.
  • the time between scans or the cycle time will be the dwell time plus the inter-scan-delay-time plus the ion residence time.
  • the cycle time required to perform at least an MS scan for each one of the 100 precursors in the MRM list is approximately 10.2 seconds (as opposed to 1.2 seconds per cycle in the absence of the FAIMS).
  • only one MS scan per precursor ion can be made across a 12-second wide LC peak.
  • WO 2009/091933 A2 relates to systems and methods for determining composition of chemical constituents in a complex mixture.
  • JP 2009 002815 A relates to an ion mobility spectrometer.
  • WO 2013/140132 A2 relates to a method of analysing ions, a method of mass spectrometry, an analytical instrument for analysing ions and a mass spectrometer.
  • the inventors describe, in this disclosure, features of second-generation FAIMS apparatuses which can be coupled with a mass spectrometer, thereby enabling "intelligent" MRM data-dependent acquisition techniques and other analysis techniques that can analyze significantly more isolations per second than would be otherwise possible in a LC-FAIMS-MS apparatus.
  • the above-described limitations associated with a conventional FAIMS coupled to a mass spectrometer can be avoided with the new generation FAIMS devices such that the FAIMS analyzer no longer restricts ion current when situated between an ESI ion source and the MS inlet.
  • the novel FAIMS apparatuses can be operated in a "non-dispersive" mode (for example, both CV and DV OFF or with a symmetric voltage waveform or an asymmetric waveform of low amplitude) according to which the FAIMS device acts as annular ion transport channel and yields sensitivity nearly identical to having no FAIMS device between the ESI and MS inlet.
  • This feature provides the option to "intelligently” apply the ion filtering function of FAIMS (i.e., the function provided in "dispersive" mode operation) along analyte-eluting regions of the LC gradient.
  • a survey mass spectrum can be obtained without any alteration to LC-FAIMS-MS hardware.
  • a second-generation FAIMS apparatus in "non-dispersive" mode, all ion species may be delivered to a coupled mass spectrometer without bias and in sufficient quantities so as to enable generation of survey mass analyses similar to those which may be obtained with a conventional LC/MS system.
  • the FAIMS may be set to an "on" operating mode in which ions can be selectively filtered according to their mobility behavior within the FAIMS apparatus.
  • a method of operating a system comprising a chromatograph operable to separate sample solutions into fractions, an ion source operable to ionize components of the fractions and a mass spectrometer operable to detect the ions, wherein the method comprises: (a) providing a list comprising respective entries for each of two or more precursor ion species of interest comprising respective precursor-ion m / z ratios; (b) performing a first analysis of a sample comprising: (b1) separating the sample into sample fractions using the chromatograph; (b2) generating a plurality of fraction ion species from each fraction using an ion source; (b3) transmitting the plurality of fraction ion species through an ion mobility spectrometer operated in non-dispersive mode to the mass spectrometer; and (b4) detecting an ion abundance at each of a plurality m / z ratios within each fraction using the mass spectrometer;
  • the sub-step (b3) of transmitting the plurality of fraction ion species through an ion mobility spectrometer operated in non-dispersive mode may comprise transmitting said plurality of fraction ion species through a high field asymmetric waveform ion mobility spectrometry (FAIMS) spectrometer.
  • FIMS high field asymmetric waveform ion mobility spectrometry
  • the subsequent operation of the FAIMS spectrometer in dispersive mode may comprise transmitting the precursor-ion species within a gas having a gas flow rate through an annular separation region of the FAIMS spectrometer from an ion inlet port to an ion exit port, wherein the gas flow rate and a flow path length between the ion inlet and ion exit ports are such that a residence time of the precursor-ion species within the FAIMS spectrometer is less than or equal to 10 milliseconds.
  • the entries of the provided list may include FAIMS operating parameters necessary for causing the FAIMS spectrometer to preferentially transmit the various precursor ion species therethrough.
  • the FAIMS operating parameters may include values for an asymmetric oscillatory dispersion voltage (DV) and a non-oscillatory compensation voltage (CV) to be applied across electrodes of the FAIMS spectrometer.
  • Such operating parameters may vary according to the particular ion species to be preferentially transmitted through the FAIMS spectrometer.
  • the operation of the FAIMS spectrometer in non-dispersive mode may comprise transmitting the ion species therethrough in the absence of application of both the CV and the DV to the electrodes.
  • the operation of the FAIMS spectrometer in non-dispersive mode may comprise transmitting the ion species therethrough during the application of a symmetric oscillatory waveform to the electrodes.
  • ion species of interest may co-elute; in other words, either the ion-signal-acquisition time (AT) or the loss-of-ion-signal time (LT) corresponding to a first m / z ratio may occur between the AT and LT corresponding to a second m / z ratio.
  • the sub-steps (i)-(iii) of sub-step (d4) listed above may repeat or iterate such that the method causes alternating (or cycled) transmission and fragmentation of ions of each m / z ratio.
  • the step (b) of transmitting the first portion of the sample fraction through an ion mobility spectrometer may comprise transmitting said first portion of the sample fraction through a high field asymmetric waveform ion mobility spectrometry (FAIMS) spectrometer.
  • the subsequent operation of the FAIMS spectrometer in dispersive mode may comprise operating the FAIMS spectrometer under application of an asymmetric oscillatory dispersion voltage (DV) and a non-oscillatory compensation voltage (CV) across electrodes of the FAIMS spectrometer, wherein said applied DV and CV are chosen so as to preferentially transmit ions of the first precursor ion species through the FAIMS spectrometer.
  • DV asymmetric oscillatory dispersion voltage
  • CV non-oscillatory compensation voltage
  • the operation of the FAIMS spectrometer in dispersive mode may comprise transmitting the first precursor-ion species within a gas having a gas flow rate through an annular separation region of the FAIMS spectrometer from an ion inlet port to an ion exit port, wherein the gas flow rate and a flow path length between the ion inlet and ion exit ports are such that a residence time of the first precursor-ion species within the FAIMS spectrometer is less than or equal to 10 milliseconds.
  • the operation of the FAIMS spectrometer in non-dispersive mode may comprise transmitting the ion species therethrough in the absence of application of both the CV and the DV to the electrodes. In some other embodiments, the operation of the FAIMS spectrometer in non-dispersive mode may comprise transmitting the ion species therethrough during the application of a symmetric oscillatory waveform to the electrodes.
  • the FAIMS operating parameters, including the CV and DV values required to preferentially transmit various ion species may be provided in the list entries. Further, various mass spectrometer operating parameters may be provided in the list entries.
  • steps (d2) and (d3) may be held conditional upon the continued above-threshold detection of ions at the m / z ratio corresponding to the first precursor ion species of interest immediately after the ion mobility spectrometer is changed to dispersive operation in step (d1). If the abundance at the m / z ratio corresponding to the first precursor ion species of interest should be below the threshold value immediately after the ion mobility spectrometer is changed to dispersive operation, then the corresponding m / z ratio may be added to a list of m / z ratios to be temporarily excluded from fragmentation (an exclusion list). Likewise, the execution of steps (d1) through (d3) listed above may be held conditional upon the m / z ratio corresponding to the first precursor ion species of interest being absent from such an exclusion list.
  • the FAIMS apparatus acts as a passive device that non-selectively transmits all ions.
  • One means to implement such a “non-dispersive" operating mode is to cease application of the FAIMS dispersion voltage (DV) and compensation voltage (CV) to the FAIMS electrodes that define a FAIMS analytical gap.
  • DV FAIMS dispersion voltage
  • CV compensation voltage
  • Other alternative means of implementing the FAIMS "non-dispersive" mode are also possible.
  • voltage may continue to be applied across the FAIMS electrodes but the applied voltage may configured with a reduced amplitude that is insufficient to cause FAIMS separation or may be changed from its usual asymmetric form to a symmetric voltage form (such as a sinusoidal or sawtooth voltage).
  • a FAIMS "on" operating mode may be defined in which DV and CV are applied to the FAIMS electrodes so as to cause the FAIMS apparatus to transmit certain selected ion species therethrough while neutralizing others.
  • on m1 represents a FAIMS operating mode in which the applied DV and CV are such that ion species having ion mobility properties corresponding to the ion mobility properties of the analyte ion species m1 are transmitted completely through the FAIMS apparatus while other ion species are neutralized and eliminated.
  • the operating mode of the FAIMS apparatus is "on m1"
  • the ion species m1 species if present, will be transmitted through the FAIMS apparatus and most other (but possibly not all) ion species will be prevented from passing completely through the FAIMS apparatus.
  • the other operating modes, "on m2", “on m3” are defined similarly, mutatis mutandis.
  • FIG. 5A illustrates a perspective sectional view (a quarter section view) of a modified FAIMS apparatus 201 as recently described in U.S. Patent No. 8,664,593 which is assigned to the assignee of the present invention.
  • the illustration in this figure is doubly-cutaway view that is cut away in a plane (the x - z plane) that includes the cylindrical axis 177 of the FAIMS inner electrode 165 and is also cut away in a plane (the y - z plane) that is perpendicular to the cylindrical axis 177 .
  • Each such sectional plane bisects the overall FAIMS apparatus 201 and, thus, the view shown in FIG. 5A is a quarter-section view.
  • FIG. 5A is a quarter-section view.
  • FIG. 5B illustrates a cross-section view (both upper and lower diagrams of FIG. 5B ) of the entrance plate and a portion of the outer electrode of the FAIMS apparatus of FIG. 5A .
  • FIG. 5B also schematically illustrates (lower diagram only) flow vectors within the gas expansion chamber 111 of the apparatus 201 .
  • the expansion chamber 111 of the apparatus 201 forms a recess within the entrance plate 120 in a fashion so as to circumferentially surround the ion inlet orifice 152 .
  • the expansion chamber recess is provided such that a portion of the walls of the ion inlet orifice 152 protrudes into the expansion chamber 111 so as to form a ring 119 that circumferentially surrounds a portion of the ion inlet orifice 152 .
  • the space between the entrance plate 120 and the inlet end 32 of the ion inlet orifice comprises a narrow gap 126 between the entrance plate and the inlet end of the ion inlet orifice.
  • the entrance plate 120 is configured such that an overlap portion 128 of a face of the entrance plate that bounds the expansion chamber 111 extends beyond the expansion chamber so as to also face the ring portion 119 of the walls of the ion inlet orifice 152 .
  • gas that enters the expansion chamber 111 through gas conduits 113 is caused to flow around the circumference of the ring 119 and then to flow into and through the gap 126 .
  • the apparatus 201 is configured such that the width of the gap 126 is significantly less than the width of the expansion chamber 111 , wherein the width of the gap is measured between the entrance plate 120 and the inlet end 32 of the ion inlet orifice 152 and the width of the chamber 111 is measured between the facing surfaces of the entrance plate 120 and the outer electrode 170 that bound the chamber. Because of these different widths, the gas pressure and flow velocity are both caused to increase as the gas flows into the gap.
  • the increased-velocity gas flow then enters the inlet end 32 of the ion inlet orifice 152 through the entirety of the gap 126 that circumferentially surrounds the inlet end of the ion inlet orifice 152 .
  • Ions pass through the aperture 117 in the entrance plate and then cross the gap 126 and pass into the ion inlet orifice 152 where they are entrained in the gas flow.
  • the overlap portion 128 of the entrance plate confines the gas to the gap 126 and enables the increase in the gas flow velocity.
  • the increased gas flow velocity and orifice wall curvature enable the Coand effect within the analytical gap 175 .
  • the wall curvature also plays an important role in delaying "flow separation" such that the gas streamlines remain attached to the outer electrode surface within the analytical gap.
  • the increased gas flow velocity produced by the squeezing of the gas flow into the gap 126 causes a high-velocity jet to form against the convexly curved interior walls of the ion inlet orifice 152 , thereby causing the high velocity gas to follow the curved surface of the walls in accordance with the Coand effect.
  • the high velocity gas flow (and, consequently, the majority of the gas itself) is diverted into the analytical gap 175 so as to avoid impact with the inner electrode 165 .
  • the majority of the entrained ions are carried along with the gas, thereby improving the ion throughput through the FAIMS apparatus.
  • the curvature of the interior walls of the ion inlet orifice 152 of the FAIMS apparatus 201 differs from the curvature of the walls of the inlet orifice 151 of the FAIMS apparatus 109 ( FIGS. 2-3 ) in that the walls of the inlet orifice 152 comprise different radii of curvature in different cross sections.
  • the radius of curvature is of the wall is r 1 whereas, in the y - z cross section oriented perpendicular to the axis 177 , the radius of curvature is r 2 , where r 1 ⁇ r 2 .
  • diversion of the gas and ion flow away from the inner electrode 165 is desirable in order to prevent unwanted neutralization of ions at the electrode surface
  • diversion of the gas and ions in a direction parallel to the electrode axis 177 can cause unnecessary spreading of the gas and ion plume as evidenced by the results in the lower portion of FIG. 6 .
  • a mass analyzer of the mass spectrometer repeatedly performs survey scans so as to monitor for the presence of at least one of the various diagnostic parent ion species of interest.
  • the detected intensity of one of the diagnostic parent ion species will breach a predetermined threshold level, represented by horizontal line 202 in FIGS. 10A-10B .
  • the above-outlined sequence of operations is represented by steps 306-312 of the method 300 depicted in FIG. 13 . These steps are described in greater detail below.
  • peak 200 corresponds to the detection of the ion species m1.
  • the FAIMS apparatus configuration is changed from "non-dispersive" mode to "on m1" operating mode so that only the ion species m1 will be transmitted to the mass spectrometer and be detected during the remaining time period corresponding to peak 200 .
  • This operation corresponds to step 314 of the method 300 depicted in FIG. 13 . Accordingly, as schematically illustrated in the bottom portions of FIGS.
  • the CV and DV of the FAIMS waveform are set, in this step, so as to transmit ions of the m1 ion species, if present, completely through the FAIMS while neutralizing ions that have differential ion mobility properties that are not similar to those of ion species m1.
  • any ions species including ion species m1 (if present), having the ion mobility properties corresponding to the selected DV and CV progress through the FAIMS apparatus from the ion inlet orifice to the ion outlet orifice without neutralization while other ions are neutralized in the FAIMS apparatus.
  • the mass analyzer receives the first of the ions completely transmitted through the FAIMS apparatus after the onset of the FAIMS "on m1" mode.
  • the ions generated by an ion source and transmitted to the mass spectrometer through the FAIMS apparatus may be considered to be potential precursor ions for a subsequent ion fragmentation or ion reaction step (step 320 ).
  • step 312 the mass-to-charge ratio of ( m / z ) 1 is added to the dynamic exclusion list such that a waiting period is set.
  • step 326 the method 300 returns to step 310 to search for another ion species having an abundance above threshold and an m / z ratio that is not on the exclusion list.
  • the ion exclusion list represents a list of ion species m / z ratios that will be temporarily excluded from selective transmission through the FAIMS to the mass spectrometer.
  • the mass analyzer will, in steps 308-312 , automatically ignore ion species of this mass-to-charge ratio and the species m1 will be excluded from FAIMS isolation (in step 314 ) because the isobaric interference species is considered to be present in the ion stream.
  • FIG. 11 illustrates a hypothetical situation of two well-resolved chromatographic peaks, peaks 201 and 203 , where each such peak corresponds to elution of a single respective analyte compound, corresponding to ion species m1 and ion species m2 as shown.
  • An initial survey chromatographic experiment can be used to identify the elution start time 206 and the elution end time 208 of the first eluting analyte and the elution start time 210 and the elution end time 212 of the other analyte.
  • the FAIMS apparatus is maintained in its "non-dispersive" condition.
  • FIG. 11 illustrates a hypothetical situation of two well-resolved chromatographic peaks, peaks 201 and 203 , where each such peak corresponds to elution of a single respective analyte compound, corresponding to ion species m1 and ion species m2 as shown.
  • step 402 of the method 400 information pertaining to the various diagnostic analyte of species of interest may be retrieved or input, either from an electronic storage device are from user data entry.
  • the retrieved information comprises at least a list of respective mass-to-charge ( m / z ) values, as expected to be generated by an ionization source, of the various analyte species of interest.
  • the retrieved information may further comprise information pertaining to product ion species to be formed by reaction or fragmentation of each respective diagnostic ion species generated by the ion source and may further include mass spectrometer operational parameter settings required to detect or fragment the ions.
  • the information may also include parameters pertaining to FAIMS settings to be employed in conjunction with the detection of each such ion species.
  • Such FAIMS settings may include various compensation voltage (CV) and dispersion voltage (DV) settings to be used so as to cause the FAIMS apparatus to transmit each respective diagnostic ion species completely through the FAIMS apparatus to the mass spectrometer while simultaneously neutralizing and eliminating other ion species.
  • CV compensation voltage
  • DV dispersion voltage
  • a preliminary survey chromatographic experimental run is performed as described above.
  • the survey may determine that not all ion species of interest are present in the sample. Accordingly, in step 406 , the list of analyte ion species to be searched for may be modified, based on information obtained from the prior survey. Since the survey data will include information relating to the detected abundance of various ions versus retention time, a list of elution start times and elution end times (such as the elution start times 206 and 210 and the elution end times 208 and 212 illustrated in FIG.; 11 ) may be derived from the survey data and recorded in step 406 .
  • each of the set of elution start times and the set of elution end times may be sorted according to increasing retention time in step 406 .
  • these derived elution start and elution end times do not exactly correspond to actual beginning and ending times of emission of compounds from a chromatographic column. Instead, the derived elution start time and elution end time discussed herein are determined from the points at which the measured ion abundances cross threshold values 211 ( FIG. 11 ).
  • the subsequent steps 408-438 of the method 400 ( FIG. 14 ) comprise an iterated loop of steps which relate to a subsequent LCMS-FAIMS-MS/MS experimental run, using a system having a FAIMS apparatus coupled to a mass spectrometer.
  • the LCMS-FAIMS-MS/MS experimental run makes use of data obtained in the prior survey experiment, as previously described.
  • a determination is made (step 408 ) as to whether the execution of the set of analyses is finished, either because the list of analytes of interest (possibly as revised in step 406 ) has been exhausted or because a time limit has been reached. If it is determined that the execution of analyses is finished, then the method 400 terminates or exits at step 409 ; otherwise, execution continues at step 410 .
  • the method 400 as shown in FIG. 14 includes optional steps and execution pathways - indicated by dashed lines - that may be executed in case the chromatography elution times are not sufficiently reproducible between the initial survey experiment and the subsequent experiment including FAIMS ion filtering. If the chromatography results are adequately reproducible, then the method 400 may follow the set of general steps and flow pathways indicated by solid lines - specifically, steps 408-413 followed by the possibly-iterated set of three steps 420 , 421 and 426 followed by step 438 . If the chromatography results are considered to be not adequately reproducible, then adjusted elution start and elution end times may be obtained during the course of the post-survey chromatography.
  • steps 408-412 are executed and followed by the possibly-iterated set of two steps 414 and 416 after which these steps are followed by step 418 which is then followed by the possibly-iterated set of steps 420 , 421 , 422 and 424 , which are then followed by steps 428-438 .
  • the step 413 of the method 400 is a waiting step in which execution of the method 400 is delayed until a time that is determined in accordance with the elution start time of the chosen analyte.
  • the delay may last until the experimental retention time advances so as to equal or exceed the elution start time of the next eluting analyte ion species, after which step 420 is executed.
  • the delay may last a shorter period such that the mass spectrometer precursor ion detection step 414 is executed prior to the previously determined elution start time of the chosen analyte, thereby allowing earlier-than-expected elution to be detected.
  • steps 414 and 416 are repeated until the detected intensity of ions having the m / z ratio of the chosen analyte breaches a threshold level.
  • the time at which the threshold is exceeded (here termed "signal-acquisition time”) is then recorded in step 418 .
  • a set of mass spectrometer operation steps including ion fragmentation (or other ion reaction) in step 420 and ion detection in step 421 are iterated until a stopping condition is reached. If the reproducibility of the chromatography is trusted, then steps 420 , 421 and 426 are repeatedly executed until the actual experimental time equals or exceeds the expected elution end time of the analyte ion species under consideration. Otherwise, if the reproducibility of the chromatography results is considered to be insufficiently adequate to permit the previously-determined elution end time to be used as the stopping condition, then steps 420-424 are repeated until the detected intensity of precursor ions drops below a threshold.
  • the FAIMS apparatus retains its setting, as set in step 412 , so as to transmit the selected precursor ion species (ion species m1, for example) and to neutralize all or most other ion species.
  • a mass filter stage of the mass spectrometer (for example, Q1) may be set so as to transmit, to a fragmentation or other ion reaction cell, a batch of ions comprising only ion species having a mass-to-charge ( m / z ) ratio value that is substantially equal to the m / z value of the selected ion species.
  • the selected ion species thus comprises a precursor ion species that is fragmented or otherwise reacted in the fragmentation or reaction cell in step 421 so as to generate product ions, in known fashion. If the execution pathway of the method 400 proceeds as shown by the dashed lines, then the step 421 of detecting product ions is followed by the step 422 of detecting analyte precursor ions so as to detect, in real time, if the elution of the selected analyte has attained its effective end time such that the detected intensity of the analyte precursor ions has dropped below a threshold value (as determined in step 424 ).
  • step 424 the time at which the detected intensity has fallen below the threshold is noted in step 428 as "loss-of-signal time" with respect to the particular analyte.
  • the "signal-acquisition time” and “loss-of-signal time” are then compared, in step 430, to the expected elution start time end elution end time, respectively, pertaining to the chosen analyte, where these expected times are as determined in the prior survey experiment.
  • FIG. 12 illustrates a situation that is similar to that shown in FIG. 11 except that the analyte compounds that give rise to ion species m3 and to ion species m4 partially co-elute.
  • a preliminary survey chromatographic experiment can determine that the elution start time and end time, as determined by threshold crossings, of peak 205 occur at time 214 and 216, respectively.
  • the survey experiment can determine that the elution start time and end time of peak 207 occur at time 218 and 220, respectively.
  • the abundance of both ion species m3 and m4 is above threshold.
  • an associated control system may be configured to operate the mass spectrometer so as fragment or otherwise react the precursor ions so as to generate product ions (possibly after isolation of the precursor ions) and to store data relating to the product ions generated from the precursor ions corresponding to the particular analyte.
  • the system time e.g., experimental run time
  • the FAIMS apparatus may be re-configured so as to transmit the next analyte on the list to the mass spectrometer and the process repeats.
  • any form of gas inlet could suffice, such as for example, gas inlet "apertures”.
  • gas inlet is described herein as an "orifice”, it could equally take the form of or be described as an "aperture” or, in some embodiments, a "conduit”.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Electrochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)

Claims (14)

  1. Procédé permettant de faire fonctionner un système comprenant un chromatographe servant à séparer des solutions d'échantillon en fractions, une source d'ions servant à ioniser des composants des fractions, et un spectromètre de masse servant à analyser et à détecter les ions, le procédé consistant à :
    (a) fournir une valeur seuil d'abondance et une liste comprenant des entrées respectives pour chacune d'au moins deux espèces ioniques précurseurs d'intérêt comprenant des rapports m/z précurseur-ion respectifs ;
    (b) transmettre, à travers un spectromètre de mobilité ionique, une première partie d'une fraction d'échantillon comprenant une pluralité d'espèces ioniques de fractions d'échantillon au spectromètre de masse, le spectromètre de mobilité ionique fonctionnant en mode non dispersif ;
    (c) détecter, à l'aide du spectromètre de masse, une abondance d'ions respective au niveau de chacun d'une pluralité de rapports m/z de fractions d'échantillon ; et
    (d) lors de la détection d'une abondance d'ions supérieure au seuil selon un rapport m/z de fractions d'échantillon correspondant à une première des espèces ioniques précurseurs d'intérêt :
    (d1) introduire une seconde partie de la fraction d'échantillon dans le spectromètre de mobilité ionique, le spectromètre de mobilité ionique fonctionnant en mode dispersif de telle sorte que les ions de la première espèce ionique précurseur sont transmis de préférence au spectromètre de masse à travers le spectromètre de mobilité ionique ;
    (d2) fragmenter les ions transmis de façon préférentielle, de manière à générer un premier ensemble d'espèces d'ions produits ; et
    (d3) détecter le premier ensemble d'espèces d'ions produits à l'aide du spectromètre de masse.
  2. Procédé selon la revendication 1, dans lequel l'étape (b) de transmission de la première partie de la fraction d'échantillon à travers un spectromètre de mobilité ionique comprend la transmission de ladite première partie de la fraction d'échantillon à travers un spectromètre de mobilité ionique en champ intense à forme d'onde asymétrique (FAIMS).
  3. Procédé selon la revendication 2, dans lequel l'étape (d1) d'introduction de la seconde partie de la fraction d'échantillon dans le spectromètre de mobilité ionique fonctionnant en mode dispersif comprend le fonctionnement du spectromètre FAIMS (201) sous application d'une tension de dispersion (DV) oscillatoire asymétrique et d'une tension de compensation (CV) non oscillatoire aux bornes des électrodes du spectromètre FAIMS (201), lesdites DV et CV appliquées étant choisies de façon à transmettre de préférence les ions de la première espèce ionique précurseur à travers le spectromètre FAIMS (201).
  4. Procédé selon la revendication 3, dans lequel l'étape (b) de transmission de la première partie de la fraction d'échantillon à travers le spectromètre de mobilité ionique fonctionnant en mode non dispersif comprend la transmission de la première partie de la fraction d'échantillon à travers le spectromètre FAIMS (201) en l'absence d'application de la CV et de la DV aux électrodes.
  5. Procédé selon la revendication 3, dans lequel l'étape (b) de transmission de la première partie de la fraction d'échantillon à travers le spectromètre de mobilité ionique fonctionnant en mode non dispersif comprend la transmission de la première partie de la fraction d'échantillon à travers le spectromètre FAIMS (201) pendant l'application d'une forme d'onde oscillatoire symétrique aux électrodes.
  6. Procédé selon la revendication 3, dans lequel la fourniture de la liste comprenant des entrées respectives pour chacune d'au moins deux espèces ioniques précurseurs d'intérêt comprend la fourniture d'entrées de la liste, chaque entrée comprenant des paramètres FAIMS nécessaires pour amener le spectromètre FAIMS (201) à transmettre de préférence les espèces ioniques précurseurs respectives.
  7. Procédé selon la revendication 6, dans lequel la fourniture de la liste comprenant des entrées respectives pour chacune d'au moins deux espèces ioniques précurseurs d'intérêt comprend en outre la fourniture des entrées, chaque entrée incluant le rapport m/z des espèces ioniques précurseurs respectives d'intérêt.
  8. Procédé selon la revendication 1, dans lequel l'étape (d1) comprend en outre la détection d'une abondance d'ions, par le spectromètre de masse, dans un rapport m/z correspondant à la première espèce ionique précurseur d'intérêt, et dans lequel la réalisation ultérieure des étapes (d2) et (d3) est subordonnée à ce que ladite abondance détectée dans ledit rapport m/z correspondant soit supérieure au seuil.
  9. Procédé selon la revendication 8, comprenant en outre, si l'abondance détectée dans ledit rapport m/z correspondant n'est pas supérieure au seuil, l'ajout dudit rapport m/z correspondant à une liste de rapports m/z à exclure temporairement de la fragmentation.
  10. Procédé selon la revendication 1, dans lequel la réalisation des étapes (d1) à (d3) est subordonnée à ce que le rapport m/z correspondant à la première espèce ionique précurseur d'intérêt soit absent d'une liste de rapports m/z qui doivent être temporairement exclus de la fragmentation.
  11. Procédé selon la revendication 1, consistant en outre à :
    (e) transmettre, à travers le spectromètre de mobilité ionique, une première partie d'une seconde fraction d'échantillon au spectromètre de masse, le spectromètre de mobilité ionique fonctionnant en mode non dispersif ;
    (f) détecter, à l'aide du spectromètre de masse, une abondance d'ions respective au niveau de chacun d'une pluralité de rapports m/z de secondes fractions d'échantillon ; et
    (g) lors de la détection d'une abondance d'ions supérieure au seuil dans un rapport m/z de secondes fractions d'échantillon correspondant à un second rapport m/z correspondant à l'espèce ionique précurseur d'intérêt :
    (g1) introduire une seconde partie de la seconde fraction d'échantillon dans le spectromètre de mobilité ionique, le spectromètre de mobilité ionique fonctionnant en mode dispersif de telle sorte que les ions de la seconde espèce ionique précurseur sont transmis de préférence au spectromètre de masse à travers le spectromètre de mobilité ionique ;
    (g2) fragmenter les ions transmis de façon préférentielle, de manière à générer un second ensemble d'espèces d'ions produits ; et
    (g3) détecter le second ensemble d'espèces d'ions produits à l'aide du spectromètre de masse.
  12. Procédé selon la revendication 11, dans lequel l'étape (b) de transmission de la première partie de la fraction d'échantillon et l'étape (e) de transmission de la première partie de la seconde fraction d'échantillon à travers le spectromètre de mobilité ionique comprend la transmission desdites premières parties à travers un spectromètre de mobilité ionique en champ intense à forme d'onde asymétrique (FAIMS).
  13. Procédé selon la revendication 12, dans lequel :
    l'étape (d1) d'introduction de la seconde partie de la fraction d'échantillon dans le spectromètre de mobilité ionique fonctionnant en mode dispersif comprend le fonctionnement du spectromètre FAIMS (201) sous application d'une première tension de dispersion (DV) oscillatoire asymétrique et d'une première tension de compensation (CV) non oscillatoire aux bornes des électrodes du spectromètre FAIMS (201), lesdites premières DV et CV appliquées étant choisies de façon à transmettre de préférence les ions de la première espèce ionique précurseur à travers le spectromètre FAIMS (201) ; et
    l'étape (g1) d'introduction de la seconde partie de la seconde fraction d'échantillon dans le spectromètre de mobilité ionique fonctionnant en mode dispersif comprend le fonctionnement du spectromètre FAIMS (201) sous application d'une seconde DV et d'une seconde CV aux bornes des électrodes du spectromètre FAIMS (201), lesdites secondes DV et DV appliquées étant choisies de façon à transmettre de préférence les ions de la seconde espèce ionique précurseur à travers le spectromètre FAIMS (201).
  14. Procédé selon la revendication 2, dans lequel le fonctionnement du spectromètre FAIMS (201) en mode dispersif comprend la transmission de la première espèce ionique précurseur dans un gaz présentant un débit de gaz dans une région de séparation annulaire (175) du spectromètre FAIMS (201), depuis un orifice d'entrée d'ions (152) vers un orifice de sortie d'ions (185), le débit de gaz et une longueur de trajet d'écoulement entre les orifices d'entrée et de sortie d'ions étant tels que le temps de séjour de la première espèce ionique précurseur dans le spectromètre FAIMS (201) est inférieur ou égal à 10 millisecondes.
EP17185084.5A 2014-06-13 2015-06-12 Procédés de fonctionnement d'un système comprenant un spectromètre de masse, spectromètre de mobilité ionique et chromatographe Active EP3270153B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201462012063P 2014-06-13 2014-06-13
EP15171949.9A EP2955515B1 (fr) 2014-06-13 2015-06-12 Procédés pour faire fonctionner un système comprenant un spectromètre de masse, spectromètre de mobilité ionique et chromatographe

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
EP15171949.9A Division EP2955515B1 (fr) 2014-06-13 2015-06-12 Procédés pour faire fonctionner un système comprenant un spectromètre de masse, spectromètre de mobilité ionique et chromatographe
EP15171949.9A Division-Into EP2955515B1 (fr) 2014-06-13 2015-06-12 Procédés pour faire fonctionner un système comprenant un spectromètre de masse, spectromètre de mobilité ionique et chromatographe

Publications (2)

Publication Number Publication Date
EP3270153A1 EP3270153A1 (fr) 2018-01-17
EP3270153B1 true EP3270153B1 (fr) 2019-07-24

Family

ID=53397925

Family Applications (2)

Application Number Title Priority Date Filing Date
EP17185084.5A Active EP3270153B1 (fr) 2014-06-13 2015-06-12 Procédés de fonctionnement d'un système comprenant un spectromètre de masse, spectromètre de mobilité ionique et chromatographe
EP15171949.9A Active EP2955515B1 (fr) 2014-06-13 2015-06-12 Procédés pour faire fonctionner un système comprenant un spectromètre de masse, spectromètre de mobilité ionique et chromatographe

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP15171949.9A Active EP2955515B1 (fr) 2014-06-13 2015-06-12 Procédés pour faire fonctionner un système comprenant un spectromètre de masse, spectromètre de mobilité ionique et chromatographe

Country Status (2)

Country Link
US (2) US9500624B2 (fr)
EP (2) EP3270153B1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170254777A1 (en) * 2016-02-18 2017-09-07 Waters Technologies Corporation Method to improve the identification, quantification and spatial localization of multiply charged molecules in biological samples using ion mobility information
EP4300540A3 (fr) 2016-04-02 2024-03-27 DH Technologies Development Pte. Ltd. Système et procédé de filtrage d'ions à haute mobilité
US10429364B2 (en) * 2017-01-31 2019-10-01 Thermo Finnigan Llc Detecting low level LCMS components by chromatographic reconstruction
CN111052301B (zh) * 2017-08-31 2024-01-02 Dh科技发展私人贸易有限公司 用以改进ms/ms动态范围的动态平衡时间计算
US11293898B2 (en) * 2020-02-06 2022-04-05 Thermo Finnigan Llc Duty cycle improvement for a mass spectrometer using ion mobility separation
CN117597583A (zh) * 2021-03-18 2024-02-23 康博国际有限公司 检测和定量体液样品的大量分子生物标志物的方法和系统
EP4089408A1 (fr) * 2021-05-14 2022-11-16 Thermo Finnigan LLC Recirculation d'écoulement pour l'amélioration de la séparation de mobilité
CN114088829B (zh) * 2021-11-04 2023-06-23 天津中医药大学 脱氢紫堇碱及其代谢产物的检测方法及其应用
WO2024026114A1 (fr) * 2022-07-29 2024-02-01 The General Hospital Corporation Cartographie de protéome à haut débit

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6504149B2 (en) 1998-08-05 2003-01-07 National Research Council Canada Apparatus and method for desolvating and focussing ions for introduction into a mass spectrometer
US6713758B2 (en) 1998-08-05 2004-03-30 National Research Council Of Canada Spherical side-to-side FAIMS
CA2402793C (fr) 2000-03-14 2009-06-16 National Research Council Of Canada Dispositif faims a lames a faces paralleles et procede associe
US7223967B2 (en) 2002-02-08 2007-05-29 Thermo Finnigan Llc Side-to-side FAIMS apparatus having an analyzer region with non-uniform spacing and method therefore
US7034286B2 (en) 2002-02-08 2006-04-25 Ionalytics Corporation FAIMS apparatus having plural ion inlets and method therefore
US6787765B2 (en) 2002-02-08 2004-09-07 Ionalytics Corporation FAIMS with non-destructive detection of selectively transmitted ions
US6958473B2 (en) * 2004-03-25 2005-10-25 Predicant Biosciences, Inc. A-priori biomarker knowledge based mass filtering for enhanced biomarker detection
US7274014B2 (en) 2004-11-24 2007-09-25 Thermo Finnigan Llc Apparatus and method for adjustment of ion separation resolution in FAIMS
US8440968B2 (en) * 2005-02-14 2013-05-14 Micromass Uk Limited Ion-mobility analyser
US7608818B2 (en) * 2005-04-29 2009-10-27 Sionex Corporation Compact gas chromatography and ion mobility based sample analysis systems, methods, and devices
US7468511B2 (en) 2006-06-13 2008-12-23 Thermo Finnigan, Llc FAIMS electrodes with lateral ion focusing
JP5125248B2 (ja) * 2007-06-22 2013-01-23 株式会社日立製作所 イオンモビリティ分光計
US7858934B2 (en) 2007-12-20 2010-12-28 Thermo Finnigan Llc Quadrupole FAIMS apparatus
US7884318B2 (en) * 2008-01-16 2011-02-08 Metabolon, Inc. Systems, methods, and computer-readable medium for determining composition of chemical constituents in a complex mixture
US8049167B2 (en) 2009-03-13 2011-11-01 University Of Florida Research Foundation, Inc. Pneumatic ion beam focusing in high-field asymmetric waveform ion mobility spectrometry (FAIMS)
US8158932B2 (en) * 2010-04-16 2012-04-17 Thermo Finnigan Llc FAIMS having a displaceable electrode for on/off operation
WO2012167254A1 (fr) 2011-06-03 2012-12-06 Dh Technologies Development Pte. Ltd. Procédé et système de réduction des interférences dans l'analyse spectrométrique de stéroïdes
US9362099B2 (en) 2012-01-05 2016-06-07 Owlstone Limited Field asymmetric ion mobility spectrometry filter
GB201205009D0 (en) 2012-03-22 2012-05-09 Micromass Ltd Multi-dimensional survey scans for improved data dependent acquisitions (DDA)
US8664593B2 (en) 2012-05-18 2014-03-04 Thermo Finnigan Llc Control of gas flow in high field asymmetric waveform ion mobility spectrometry
JP5997650B2 (ja) * 2013-04-15 2016-09-28 株式会社日立ハイテクノロジーズ 分析システム

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Also Published As

Publication number Publication date
EP3270153A1 (fr) 2018-01-17
EP2955515B1 (fr) 2017-12-27
US9500624B2 (en) 2016-11-22
US20170074827A1 (en) 2017-03-16
EP2955515A1 (fr) 2015-12-16
US20150362461A1 (en) 2015-12-17

Similar Documents

Publication Publication Date Title
EP3270153B1 (fr) Procédés de fonctionnement d'un système comprenant un spectromètre de masse, spectromètre de mobilité ionique et chromatographe
US10083825B2 (en) Mass spectrometer with bypass of a fragmentation device
US11488815B2 (en) Trap fill time dynamic range enhancment
US11769654B2 (en) Two dimensional MSMS
US9881778B2 (en) Hybrid acquisition method incorporating multiple dissociation techniques
JP7241821B2 (ja) 最適化された標的を絞った分析
CA2835314A1 (fr) Spectrometre de masse
CA2628927C (fr) Spectrometre de masse
GB2551614A (en) Hybrid acquisition method incorporating multiple dissociation techniques
GB2525709A (en) Optimized multiple reaction monitoring or single ion recording method
US10041907B2 (en) Accurate mobility chromatograms
GB2604834A (en) Optimised targeted analysis

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN PUBLISHED

AC Divisional application: reference to earlier application

Ref document number: 2955515

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20180717

RBV Designated contracting states (corrected)

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

RIC1 Information provided on ipc code assigned before grant

Ipc: G01N 27/62 20060101ALI20180913BHEP

Ipc: G01N 30/72 20060101AFI20180913BHEP

Ipc: H01J 49/00 20060101ALI20180913BHEP

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20181024

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

INTC Intention to grant announced (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20190213

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AC Divisional application: reference to earlier application

Ref document number: 2955515

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602015034617

Country of ref document: DE

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1158777

Country of ref document: AT

Kind code of ref document: T

Effective date: 20190815

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20190724

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1158777

Country of ref document: AT

Kind code of ref document: T

Effective date: 20190724

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20191024

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20191024

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20191125

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20191124

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20191025

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200224

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602015034617

Country of ref document: DE

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG2D Information on lapse in contracting state deleted

Ref country code: IS

26N No opposition filed

Effective date: 20200603

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200612

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20200630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200630

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200630

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200612

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190724

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20230628

Year of fee payment: 9

Ref country code: DE

Payment date: 20230616

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20230621

Year of fee payment: 9